Sudden death due to lethal ventricular arrhythmias is a leading cause of mortality in the United States of America and throughout western civilization. It occurs unpredictably and usually without warning symptoms. Prior to the present invention, it is not believed that current methodology existed which provides adequately reliable risk stratification to identify which individuals are most in need of the limited and expensive resources required to prevent sudden cardiac death.
Sudden cardiac death (SCD) remains a public health problem in the United States with an incidence of 300,000 to 400,000 per year. SCD accounts for approximately half of all cardiac deaths. Ventricular fibrillation (VF) is the first documented rhythm in the vast majority of patients resuscitated from SCD, although holter monitoring has shown that VF is usually initiated by a period of rapid or polymorphic ventricular tachycardia (VT).
Cardiac mortality is particularly high among patients with congestive heart failure (CHF) and cardiac chamber enlargement, termed dilated cardiomyopathy (DCM). This syndrome has many etiologies including coronary artery disease, valvular heart disease, and myocarditis, although frequently no specific cause is identified. &renal death rates in these patients are as high as 25-40%.
Recent work has been directed toward identifying electrical abnormalities associated with DCM. Human studies and animal models of DCM reveal significant prolongation of action potential duration (APD) in cells isolated from failing hearts, regardless of etiology, compared to those taken from normal hearts. The plateau and terminal repolarization phases of the action potential are known to be quite labile. Membrane resistance is high at this time, and small changes in current can shift the balance toward either further repolarization or extended depolarization. It is generally believed that the longer the APD, the more labile is the repolarization process. Maintained or secondary depolarizations, also referred to as early after-depolarizations (EADs), can initiate triggered arrhythmias, including torsade de pointes, a form of polymorphic W and lead to VF. The presence of hypokalemia, hypocalcemia, hypomagnesemia, acidosis, or antiarrhythmic drugs, all common in patients with CHF, can affect either outward (repolarizing) or inward (depolarizing) currents and promote EADs.
The failing myocardium displays not only prolonged APD, but increased spatial heterogeneity of APD as well as resulting in an increase in dispersion of refractoriness. In such a substrate, a wave of depolarization is likely to encounter islands of refractory tissue, potentially leading to polymorphic ventricular arrhythmias through a mechanism of functional reentry. The cellular electrophysiologic basis for heterogeneity of APD may be multi-factorial. Regional variations in K.sup.+ current densities, particularly I.sub.W have been reported in animal models. Heterogeneity of sympathetic innervation has also been described in patients with DCM and has been correlated with dispersion of refractoriness.
A number of tests, both invasive and noninvasive, have been employed as risk stratifiers of cardiac mortality in patients with CHF. Left ventricular election fraction (LVEF) has been shown to predict mortality in patients with schemic and nonischemic DCM. However, while total mortality increases with declining LV function, the fraction of deaths that are sudden has been observed to be highest in patients with the least severe disease. Furthermore, as discussed above, the population of patients with moderate to severe LV dysfunction is huge, so risk stratification by LVEF alone is insufficient.
The value of ambulatory monitoring and detection of asymptomatic ventricular ectopic activity (VEA) has been controversial. The presence of VEA has been shown to correlate with increased risk of SCD in survivors of myocardial infarction, although the sensitivity of this test for SCD is only approximately 30% and the specificity is lower. Furthermore, in a study in which ambulatory monitoring was used to predict drug efficacy for suppression of life-threatening arrhythmias in MI survivors, patients taking the active drug had sudden death rates in excess of those in a placebo treated group, thus demonstrating the inability of ambulatory monitoring to predict drug prearrhythmia. In patients with idiopathic DCM, high grade VEA has a prevalence of roughly 50% and essentially no predictive value. Similarly, exercise testing is not believed to be particularly useful in predicting SCD, as malignant arrhythmias are rarely provoked by such tests, even in high risk patient populations.
Signal-averaged electrocardiography (SAECG), which detects low amplitude electrical activity on the tail of the QRS complex reflective of slowed conduction required for reentry, has also been studied as a noninvasive means of stratifying arrhythmic risk. This methodology is not believed to be particularly useful in the setting of a bundle branch block, a common finding among patients with DCM, as it is believed that subtle late potentials would be masked. The SAECG has been observed to be moderately predictive of inducibility to monomorphic VT among survivors of a previous inferior MI, although less so in the setting of prior anterior MI. A number of studies have also demonstrated that the SAECG is predictive of SCD and overall mortality following an MI and in patients with nonischemic cardiomyopathy.
Electrophysiologic (EP) testing is an invasive procedure that has been observed to be highly sensitive for monomorphic VT, particularly among MI survivors with the substrate for classical reentry. EP testing is also believed to be capable of predicting drug efficacy in patients with inducible sustained monomorphic VT. Polymorphic VT and VF are often induced during EP testing as well, but are not predictive of such arrhythmias occurring clinically. Furthermore, arrhythmias are generally not inducible in SCD survivors or in patients with nonischemic DCM. Thus, EP testing is believed to have a limited role in predicting SCD, as it is invasive and lacks both sensitivity and specificity for polymorphic arrhythmias.
It is believed that heart rate variability (HRV) can function as a marker of arrhythmic risk. Reduced HRV has been shown to correlate with increased risk of SCD in MI survivors. Patients with CHF, irrespective of etiology, have also been shown to have reduced HRV compared with controls. While HRV is believed to be influenced by both sympathetic and parasympathetic modulation, it is believed that a reduction in vagal tone constitutes the mechanism by which HRV is reduced and arrhythmias are promoted among MI survivors at increased risk. It is somewhat unexpected that HRV stratifies arrhythmic risk as well as it does, given that it reflects alterations in autonomic balance, not direct changes in ventricular electrical integrity.
It is well known that congenital or acquired prolongation of the electrocardiographic QT interval is associated with an increased risk of polymorphic VT, VF, and SCD as disclosed by Keren, A. et al. "Etiology, warning signals and therapy of torsades de pointes: A study of 10 patients," Circulation, vol. 64, pp. 1167-1174, 1981; and Akhtar, M., "Clinical spectrum of ventricular tachycardia", Circulation, vol. 82, pp. 156-173, 1990. QT prolongation produced in an animal model by administration of the potassium channel blocker cesium chloride also leads to the development of EADs, triggered activity, and torsade de pointes. While these and similar observations in humans underscore the importance of altered ventricular repolarization in the incidence of SCD, QT prolongation alone is believed to lack adequate specificity to serve as a useful predictor of malignant arrhythmias, and mechanistically may not be important without accompanying electrical abnormalities.
It is believed that increased dispersion of repolarization duration is at least as important as prolongation of repolarization in the genesis of polymorphic arrhythmias. Invasive monophasic action potential (MAP) recordings have demonstrated regional inhomogeneity of APD in patients with the long QT syndrome and ventricular arrhythmias and in association with decreased fibrillation thresholds in dogs. Indirect evidence of regional differences in repolarization duration has been obtained noninvasively by body surface potential mapping. It has been proposed that the difference between maximum and miningurn QT interval measured on a 12-lead ECG, referred to herein as "QT dispersion", provides an assessment of arrhythmic risk in patients with the long QT syndrome. More recently, this measure has been evaluated in a variety of patient populations at risk for malignant arrhythmias. QT dispersion is believed to be an effective metric for risk stratification of polymorphic VT an SCD, as it is based on a mechanism directly reflective of an abnormal ventricular electrical milieu. However, several technical difficulties make the QT dispersion measurement problematic and difficult to automate. For example, it is hard to identify a reproducible morphologic point to mark the end of the T wave; it is also somewhat unclear whether or not to include U waves in the QT interval; and approaches for rate correction of the QT interval have been questioned. Furthermore, while the QT interval may be substantially unambiguous in a few ECG leads, computation of the QT dispersion requires accurate determination of the QT interval in all 12 standard surface leads. Manual measurement of QT dispersion is laborious, and values obtained by automated algorithms often differ significantly from those found manually.
There is emerging evidence that temporal variation of ventricular repolarization may be an important precursor to malignant arrhythmias. A number of investigators have observed alternans of T wave morphology prior to spontaneous arrhythmias in animal models, for example, as disclosed by Hellerstein, H. K. et al., "Electrical alternation in experimental coronary artery occlusion," Am. J. Physiol., vol. 160, pp. 366-374, 1950; Russell, D. C. et al. "Transmembrane potential changes and ventricular fibrillation during repetitive myocardial ischaemia in the dog", Br. Heart J., vol. 42, pp. 88-96, 1979; and Adam, D. R. et al., "Fluctuations in T-wave morphology and susceptibility to ventricular fibrillation," J. Electrocardiology, vol. 17, pp. 209-218, 1984. The mechanism of T wave alternans also has been investigated. It is believed that dispersed subpopulations of cells may be refractory on an alternate beat basis, giving risk to macroscopic electrical alternans, wavefront fractionation, and potential reentry, for example, as disclosed by Smith, I. M. et al., "Simple finite-element model accounts for wide range of cardiac dysrhythmias," PNAS, vol. 81, pp. 233-237, 1984. Alternatively, it is believed that T wave alternans may reflect alternation in action potential morphology among a subpopulation of cells, for example as disclosed by Verrier, R. L. et al., "Electrophysiologic basis for T wave alternans as an index of vulnerability to ventricular fibrillation," J. Cardiovasc. Electrophysiol., vol. 5, pp. 445-461, 1994. An algorithm to quantify the magnitude of T wave alternans also has been developed, for example as disclosed by Smith, J. M. et al., "Electrical alternans and cardiac electrical instability," Circulation, vol. 77, pp. 110-121, 1988, which has been shown to correlate with VT inducibility during EP testing and with arrhythmia-free survival, for example as disclosed by Rosenbaum, D. S., et al., "Electrical alternans and vulnerability to ventricular arrhythmias," NEJM, vol. 330, pp. 235-241, 1994. These investigators found that a chronotropic challenge by invasive atrial pacing was required to elicit sufficient T wave alternans to permit risk stratification.
In view of the importance of repolarization lability in arrhythmogenesis and the utility of heart rate variability as a risk stratifier, it is believed that QT interval variability might be abnormal in the setting of an arrhythmogenic substrate and serve as a marker of risk. Diurnal variation in QT interval has been observed for some time, for example as disclosed by Browne, K. F., "Prolongation of the QT interval in man during sleep," Am. J. Cardiol., vol. 52, pp. 55-59, 1983; and Bexton, R. S., et al., "Diurnal variation of the QT interval-influence of the autonomic nerve system," Br. Heart J., vol. 55, pp. 253-258, 1986. However, it is believed that little work has been done relating to beat-to-beat fluctuations in QT interval because of the technical difficulties in automated QT interval measurement, and particularly in separating true subtle beat-to-beat changes in QT interval from measurement noise.
Several algorithms for automated QT interval determination have been suggested that attempt to identify the point where the T wave rejoins the baseline, for example as disclosed by Laguna, P. et al., "New algorithm for QT interval analysis in 24-hour holter ECG: performance and applications," Med. & Biol. Eng. & Comp., vol. 28, pp. 67-73, 1990; Pisani, E. et al., "Performance evaluation of algorithm for QT interval measurements in ambulatory ECG recording, Comp. in Cardiol., vol. 11, pp. 459-462, 1985; and Algra, A. et al., "An algorithm for computer measurement of QT intervals in the 24 hour ECG," Comp. in Cardiol., vol. 13, pp. 117-119, 1987. However, it is believed these methods may be prone to erroneous results, even in the setting of low amplitude noise, since they depend critically on signal quality of the terminal T wave. Two reports are directed to the relationship between beat-to-beat heart rate and QT interval variability. Merri et al. studied 10 healthy volunteers and found that fluctuations in repolarization duration followed closely those in RR interval (Merri, M. et al., "Dynamic analysis of ventricular repolarization duration from 24-hour holier recordings," IEEE Trans. Biomed. Eng., vol. 40, pp. 1219-1225, 1993). On the other hand, Sarma et al. found poor coherence between RR and QT interval fluctuations in 12 patients with stable coronary artery disease (Sarma, J. S. M. et al., "Circadian and power spectral changes of RR and QT intervals during treatment of patients with angina pectoris with nadolol providing evidence for differential autonomic modulation of heart rate and ventricular repolarization" Am. J. Cardiol., vol. 74, pp. 131-136, 1994). In neither of these studies, however, were fluctuations in true QT interval measured. To avoid the above-mentioned technical difficulties, both groups analyzed the interval from the peak of the R wave to the peals of the T wave. However, this approach essentially ignores fluctuations in U waves and the terminal portion of the T wave, both of which are likely to reflect arrhythmogenic abnormalities in repolarization, such as EADs, should they occur, for example as disclosed by Jackman, W. M. et al., "Ventricular tachyarrhythmias related to early after depolarizations and triggered firing: Relationship to QT interval prolongation and potential therapeutic role for calcium channel blocking agents," J. Cardiovasc. Electrophysiol., vol. 1, pp. 170-195, 1990.
Accordingly, algorithms previously developed to measure the entire QT interval are believed to be problematic for beat-to-beat QT variability analysis. These algorithms use some morphologic feature to define the point where the T wave ends and joins the baseline, e.g., a fall in the slope below some threshold level, as disclosed by Laguna, P. et al., "New algorithm for QT interval analysis in 24-hour holter ECG: performance and applications," Med. & Biol. Eng. & Comp., vol. 28, pp. 67-73, 1990; Pisani, E. et al., "Performance evaluation of algorithm for QT interval measurements in ambulatory ECG recording, Comp. in Cardiol., vol. 11, pp. 459-462, 1985; and Algra, A. et al., "An algorithm for computer measurement of QT intervals in the 24 hour ECG," Comp. in Cardiol., vol. 13, pp. 117-119, 1987. At least one problem with such an approach related to the fact that the latter part of the T wave is generally quite flat so that any signal noise can significantly shift the point where the threshold condition is met and lead to erroneous QT interval values.